After cancer and heart disease, neurodegenerative diseases, such as Alzheimer's, Parkinson's, multiple sclerosis (MS), amythrophic lateral sclerosis (ALS), take more lives each year than any other illness. Although great progress has been made in recent years toward understanding of neurodegenerative diseases, few effective treatments and no cures are currently available. This is mainly because the blood-brain barrier (BBB) limits the delivery of the vast majority of systemically-administered drugs available to treat those diseases. The underlying hypothesis of this study is that delivery of therapeutic molecules is safe and effective through the blood-brain barrier (BBB) using Focused Ultrasound (FUS). Our preliminary results have shown that the FUS technique can induce BBB opening entirely noninvasively, selectively and be monitored with MRI at sub-millimeter resolution in vivo, both in normal mice and Alzheimer's-model mice. The primary objective of this study is thus to establish the neurotherapeutic potential of trans-BBB delivery using FUS, i.e., determine its complete safety and efficacy profiles. Once those are established, a secondary objective entails the potential for translation to the clinic, i.e., development of FUS prototypes for non-human primate and human use for future large animal and clinical assessment, respectively. The multi-disciplinary team assembled encompasses all critical specialty areas such as ultrasound engineering, Alzheimer's pathophysiology in animals and humans, histological and behavioral studies and transgenic model development as well as MR and fluorescence imaging expertise. The specific aims of the study are therefore to: 1) assess the safety of the BBB opening in the presence or absence of disease in vivo; 2) evaluate the efficacy of FUS-enhanced pharmacological therapies in vivo; and 3) build and test the FUS systems for transcranial BBB opening in non- human primates and humans. Following the proposed studies, this entirely noninvasive and highly localized BBB opening method will be tested in large animals and, ultimately, humans in conjunction with the most promising, systemically administered pharmacological agents to demonstrate its true clinical potential, for Alzheimer's or other neurodegenerative or neurological diseases.